tbuckley/cabot-search huggingface dataset:
ARTISTRY-6: Nemvaleukin alfa monotherapy in patients with advanced mucosal and cutaneous melanoma.
Authors: Jeffrey S. Weber, Richard D. Carvajal, Omid Hamid, Seung Tae Kim, Miso Kim, Ryan J. Sullivan, Dae Ho Lee, Inderjit Mehmi, Jaspreet Singh Grewal, Hyo Jin Lee, Arkadiusz Z. Dudek, Yangchun Du, Monali Desai, MD, Yan Wang, Carlos Alberto Mayo, Mark R. Middleton
Journal: Journal of Clinical Oncology (2022)

TPS9609 Background: Despite improved outcomes for melanoma patients with the introduction of checkpoint inhibitors (CPIs), ̃50% of patients do not respond. A subset of responders ultimately progress and have limited treatment options, underscoring a high unmet need for novel treatments with durable benefit. Patients with mucosal melanoma exhibit response rates and progression-free survival times ̃2 times lower than those with cutaneous melanoma. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor complex to preferentially activate CD8 + T and NK cells with minimal expansion of regulatory T cells. Nemvaleukin has been granted Orphan Drug designation for the treatment of mucosal melanoma by the FDA. In ARTISTRY-1, the intravenous (IV) recommended phase 2 dose (RP2D) of 6 µg/kg nemvaleukin monotherapy demonstrated durable antitumor activity in patients with advanced melanoma, including mucosal melanoma, previously treated with a CPI. In ARTISTRY-2, the subcutaneous (SC) RP2D of 3 mg q7d was identified demonstrating pharmacodynamic effects consistent with IV delivery. Data support further evaluation of nemvaleukin monotherapy among patients with advanced mucosal and cutaneous melanoma. Methods: ARTISTRY-6 is a phase 2, global, multicenter, open-label study. Eligible patients have had prior treatment with an anti–PD-(L)1 therapy with or without anti–CTLA-4 therapy and have an ECOG performance status of 0 or 1 and adequate hematologic reserve and hepatic and renal function. Patients with advanced cutaneous (Cohort 1) and mucosal (Cohort 2) melanoma will receive nemvaleukin at the SC and IV RP2D, respectively. Patients will receive nemvaleukin until progression or intolerable toxicity. The primary objective is to evaluate the antitumor activity of nemvaleukin monotherapy defined by overall response rate. Additional objectives include the evaluation of safety, health-related quality of life, predictive biomarkers, pharmacokinetics, immunogenicity, and pharmacodynamic effects. Clinical trial information: NCT04830124.
Clinical outcomes of immune checkpoint inhibitor (ICI) therapy among Veterans Affairs patients with colorectal cancer and discordant dMMR/MSI-H status.
Authors: James Isaacs, Aixia Guo, Vishal Vashistha, Evangelia Katsoulakis, Elizabeth Boswell, John H Strickler, Sara Ahmed, Michael J. Kelley
Journal: Journal of Clinical Oncology (2022)

3534 Background: Clinical trials have demonstrated improvements in survival with immune checkpoint inhibitors (ICIs) for advanced colorectal cancer patients with MSI-H/dMMR detected using PCR-based assays (PCR) or immunohistochemistry (IHC), respectively. MSI-H can also be assessed by next-generation sequencing (NGS). Evaluation of real-world outcomes among MSI-H patients by NGS treated with ICIs are warranted, particularly when results are discordant between these tests. Methods: The VA National Precision Oncology Program Database was accessed to select veterans with colorectal cancer and an MSI-H biomarker by NGS. Baseline patient variables, disease characteristics, and duration of ICI treatment were obtained from the VA’s Corporate Data Warehouse. Concordance between NGS and IHC or PCR testing was computed, and the response rate and duration of ICI treatment in patients with discordant test results were recorded from chart review. Results: Among 1,276 colorectal cancer patients, 71 (5.6%) were found to have MSI-H by NGS. Of these, 22 (30.1%) received ICI. Among 49 patients who did not receive ICI, 36 had stage I-III disease, 5 had limited performance status, 5 were actively being treated with chemotherapy and 3 had completely resected stage IV disease. Of the 71 patients, 29 had dMMR IHC testing, 8 had MSI-H PCR testing, 1 had both IHC and PCR testing, and 34 patients had only NGS testing. No PCR tests were discordant with NGS but 8 of 29 IHC tests were discordant. Among these 8 patients with discordant IHC MMR and MSI-H by NGS, 5 received pembrolizumab. There were 3 partial responses, 1 stable disease and 1 progressive disease. Durable responses were seen with 3 of 5 patients remaining on therapy without progression at the time of this analysis at a median follow up of 8.5 months. Conclusions: In a cohort of NGS MSI-H colorectal cancer patients, there was a high rate of discordant IHC results. Clinical benefit is seen in patients treated with ICI with discordant testing results, suggesting that NGS testing identifies patients with false negative dMMR IHC testing in the real-world clinical setting.
Constitutional <i>BRCA1</i> methylation and risk of incident triple-negative breast cancer and high-grade serous ovarian cancer.
Authors: Per Eystein Lonning, Oleksii Nikolaienko, Kathy Pan, Allison W. Kurian, Hans Petter Petter Eikesdal, Mary Pettinger, Garnet L Anderson, Ross L Prentice, Rowan T. Chlebowski, Stian Knappskog
Journal: Journal of Clinical Oncology (2022)

10509 Background: About 25% of all triple-negative breast cancer (TNBC) and 10–20% of high-grade serous ovarian cancers (HGSOC) harbor BRCA1 promoter methylation. While constitutional BRCA1 promoter methylation has been observed in normal tissues of some individuals, the potential role of normal tissue methylation as a risk factor for incident TNBC or HGSOC risk is unknown. Methods: The objective of this study was to assess potential correlation between white blood cell (WBC) BRCA1 promoter methylation and subsequent risk of incident TNBC and HGSOC. To do so, we analyzed samples from women participating in the Women’s Health Initiative (WHI) study who had not been diagnosed with either breast or ovarian cancer prior to study entrance. A total of n = 636 women developing incident TNBC and 509 women developing incident HGSOC were matched with cancer-free controls (n = 1838 and 2979) in a nested case-control design. Cancers were confirmed after central medical record review. Blood samples, collected at entry, were analyzed for BRCA1 promoter methylation by massive parallel sequencing. Associations between BRCA1 methylation and incident TNBC and incident HGSOC were analyzed by unconditional logistic regression. Results: Age at entry was 62 (median; range 50 to 79) years, with median interval to diagnosis of 9 (TNBC) and 10 (HGSOC) years. The presence of methylated BRCA1 alleles was significantly associated with higher risk of incident TNBC (OR 2.44, 95% CI 1.79–3.33; P &lt;.001) and incident HGSOC (OR 1.87, 95% CI 1.32–2.61; P &lt;.001). Restricting analyses to individuals with &gt; 5 years between sampling and cancer diagnosis yielded similar results (&gt; 5 years; TNBC: OR 2.53, 95% CI 1.81–3.54; P &lt;.001; HGSOC: OR 1.81, 95% CI 1.21–2.63; P =.003). Across individuals, methylation was not haplotype-specific, arguing against an underlying cis-acting factor. Within individuals, BRCA1 methylation was observed on the same allele, indicating clonal expansion from a single methylation event. Conclusions: Constitutional normal tissue BRCA1 promoter methylation is significantly associated with risk of incident TNBC and HGSOC with implications for prediction of these cancers not associated with germline mutations. These findings warrant further research to determine if constitutional methylation of tumor suppressor genes are pan-cancer risk factors.
A phase Ib/II study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i), in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL).
Authors: Jianyong Li, Keshu Zhou, Weiqi Nian, Guohui Cui, Jishi Wang, Xiaoping Zhang, Hong Cen, Fei Li, Shuhua Yi, Ru Feng, Chongyuan Xu, Wenbin Qian, Lihong Liu, Caixia Li, Xielan Zhao, Zi Chen, Junxiao Qiao, Hongli Zhang, Mohammad Ahmad, Yifan Zhai
Journal: Journal of Clinical Oncology (2022)

7543 Background: B-cell malignancies evade apoptosis by overexpressing BCL-2 proteins. Approved BCL-2i venetoclax requires a slow dose ramp-up to limit risk of tumor lysis syndrome (TLS) and has been associated with severe neutropenia. Investigational single-agent lisaftoclax is a novel, oral BCL-2i active against hematologic malignancies (HMs), with potentially synergistic antitumor effects when combined with other agents in B-cell malignancies. Methods: The aim of this multicenter open-label study was to evaluate dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), efficacy, pharmacokinetics (PK), and pharmacodynamics of lisaftoclax in pts with R/R CLL/SLL (per 2008 iwCLL NCI-WG guidelines). Lisaftoclax was administered orally once daily at 3 dose cohorts (400, 600, or 800 mg) every 28 days, with 15 pts in each cohort. Results: As of the data cutoff date of January 25, 2022, 45 pts had been enrolled, with a median (range) age of 58 (38-80) years. DLT and MTD were not observed. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 400 to 800 mg (average half-life: 4.2-6.6 hours). A total of 42 pts experienced any-grade treatment-related adverse events (AEs), including neutropenia (55.6%); anemia (42.2%); decreased leukocyte count (40%); thrombocytopenia (37.8%); lowered lymphocyte count (17.8%); hyperuricemia (31.1%); hypokalemia (24.4%); increased blood bilirubin (22.2%); hypertriglyceridemia (20%); diarrhea (20%); hyperphosphatemia, hypocalcemia, and decreased weight (15.6% each); increased AST (15.6%) and blood LDH (13.3%); pyrexia; and increased ALT and blood creatinine (11.1% each). A total of 28 (62.2%) pts experienced grade ≥ 3 AEs and 13 (28.9%) serious AEs. Of these, 25 (55.6% of total) and 9 (20%) were related to lisaftoclax, and 14 (31.1%) led to treatment discontinuation. One clinical TLS was reported. With a median (range) treatment of 7 (1-17) cycles and median (range) time to response of 1 (1-13) cycles, 1 of 41 evaluable pts with CLL experienced complete response (CR) and 27 with CLL/SLL achieved partial response (PR), for an objective response rate (ORR) of 68.29%. The RP2D of lisaftoclax as monotherapy was determined as 600 mg. Conclusions: BCL-2i lisaftoclax was well tolerated up to 800 mg/day. There were no significant new or unmanageable safety findings, and the ORR was 68.29%. Lisaftoclax may offer a treatment alternative for pts with R/R HMs, with a daily ramp-up schedule that may be more convenient and “user friendly.” Clinical trial information: NCT04494503.
Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: First results of the CONKO-007 trial.
Authors: Rainer Fietkau, Michael Ghadimi, Robert Grützmann, Uwe A Wittel, Lutz Jacobasch, Waldemar Uhl, Roland S. Croner, Wolf Otto Bechstein, Ulf Peter Neumann, Dirk Waldschmidt, Stefan Hubert Boeck, Nicolas Moosmann, Anke C. Reinacher-Schick, Henriette Golcher, Werner Adler, Sabine Semrau, Annett Kallies, Markus Hecht, Andrea Tannapfel, Helmut Oettle
Journal: Journal of Clinical Oncology (2022)

4008 Background: Chemotherapy (CT) is the standard of care in nonresectable locally advanced pancreatic cancer. The CONKO-007 trial studied the role of sequential CT and chemoradiotherapy (CRT). Methods: In this randomized multicenter phase III trial resectability was judged by an independent surgical board. Patients (pts) received induction chemotherapy (IC) for 3 months (3 cycles gemcitabine (Gem, 1000 mg/m² d1, 8, 15, q4w) or FOLFIRINOX (6 cycles, q2w)). After IC pts without progression were randomized to either continuing CT for another 3 months or receiving CRT (cumulative dose of 50.4Gy, single dose 1.8Gy + Gem 300 mg/m² weekly, followed by 1 cycle of Gem 1000 mg/m² at d1, 8, 15). The primary endpoint of the study was overall survival (OS) since the begin of IC. Determination of sample size calculated 590 pts to be randomized. Due to the exclusion of pts with progressive disease after IC a total of 830 pts should be enrolled. Due to delayed patient accrual the primary endpoint was changed to R0 resection rate resulting in an estimated sample size of 525 pts. Results: Between 04/2013 and 02/2021 a total of 525 pts were enrolled in 47 sites. 402 pts received IC with FOLFIRINOX and 93 pts with Gem. After IC 190 pts were excluded due to progression or toxicity, 335 were randomized, their median FU was 16 months. Hematological toxicities were significantly increased in the CRT arm, non-hematological toxicities were comparable. R0 CRM- resection rate and pCR rate was significantly higher in the CRT arm. R1-resections occurred significantly more often in the CT arm. Median progression-free survival (PFS) (HR 0.919, 95% CI 0.702-1.203, p=0.540) and OS (HR 0.964, 95% CI 0.760-1.225, p=0.766) did not differ significantly in both arms, whereas the PFS rate tended to be higher in the CRT arm after 2 years. OS rates for CRM- R0 surgery with 87.5. ± 0.05% (1y) and 67.2 ± 0.05% (2y) were significantly higher (p&lt;0.01) than for CRM+ R0 surgery with 66.7 ± 0.15% (1y) and 41.2 ± 0.1% (2y) as well as for patients without or incomplete surgery with 68.5 ± 0.03% (1y) and 26.4 ± 0.03% (2y). Conclusions: The addition of radiotherapy after IC improves the R0 CRM - resection and pCR rate without significant change in R0 resection rate (primary endpoint). Pts with R0 CRM - resections had a better prognosis compared to patients with either R0 CRM+ or incomplete or without surgery. However, this effect on resectability did not translate into a statistically significant PFS or OS benefit in the whole cohort. Clinical trial information: NCT01827553. [Table: see text]
Performance of the 2021 CKD-EPI equations without a race coefficient in a multi-racial population of adults with solid tumors: A prospective cross-sectional study.
Authors: Veronica Torres Costa E Silva, Luiz A. Gil-Jr, Lesley Inker, Renato Caires, Elerson Costalonga, George Coura-Filho, Maria Del Pilar Estevez-Diz, Gilberto Castro, Paul Mathew, Andrew Levey, Emmanuel de Almeida Burdmann
Journal: Journal of Clinical Oncology (2022)

12064 Background: We previously showed that estimated glomerular filtration rate (eGFR) based on serum creatinine (Scr)(eGFRcr) using the 2009 CKD-EPI equation performed better than Cockroft-Gault equation (CG) in solid tumor patients in Brazil (Onco-GFR Study). In that study, eGFR based on Scr and cystatin C (Scys)(eGFRcr-cys) using the 2012 CKD-EPI was the most accurate equation and suitable for use as a confirmatory test. The CKD-EPI 2009 eGFRcr and 2012 eGFRcr-cys equations include a term for race (Black vs. non-Black). The 2021 CKD-EPI eGFRcr and eGFRcr-cys equations do not include race and are now recommended in the US, but have not been assessed in a multi-racial population or in cancer patients. The aim of this study is to evaluate the performance of the 2021 CKD-EPI equations in the Onco-GFR Study. Methods: Measured GFR (mGFR) was determined using the plasma clearance of 51 Cr-EDTA. Scr and Scys assays were traceable to international standards. Results: A group of 1,200 patients recruited between April 2015 and September 2017 were included for analysis. Patients were 58.8±13.2 years, 50.8% male. Race distribution was Black participants 12.8% and non-Black participants 81.2%. Mean (SD) mGFR was 78.5±21.7 ml/min/1.73 m 2 . For eGFRcr, the overestimation of mGFR was larger for the 2021 vs. 2009 equation -10.0 vs. 8.1 ml/min/1.73m 2 , resulting in lesser accuracy 1-P30 of 22.3 vs. 19.1, but still more accurate than CG equation (1-P30 of 24.9, P = 0.05). For eGFRcr-cys, the overestimation of mGFR was larger for the 2021 vs. 2012 equation (-4.1 vs. -2.0 ml/min/1.73m 2 ). eGFRcr-cys using the 2021 equation was more accurate than eGFRcr using the 2021 equation and eGFRcys using the 2012 equation (1-P30 9.8 vs. 22.3 and 12.3, p-values &lt; 0.001 and 0.01, respectively) (Table). Conclusions: 2021 CKD-EPI eGFRcr equation race performed better than CG. 2021 CKD-EPI eGFRcr-cys performed better than 2021 eGFRcr and 2012 eGFRcys equations. Removing race from eGFR equations represents an advance and should be incorporated in cancer care. [Table: see text]
Clinical applicability of targeted next-generation sequencing for precision medicine in diffuse large B-cell lymphoma.
Authors: Dehong Huang, Yao Liu, Jieping Li, Tao Yang, Jun Liu, Chunyan Xiao, Bingling Guo, Jing Wu, Xiping Liang, Wenjun Zhang, Xin Luo, Lingqian Zhang, Ying Xiang, Qiying Li, Yingyu Nan, Xiaoxuan Wang, Furong Du, Chao Song
Journal: Journal of Clinical Oncology (2022)

e19538 Background: Comprehensive genomic analysis based on next-generation sequencing (NGS) allows a better molecular characterization of diffuse large B-cell lymphoma (DLBCL), offering a roadmap toward precision medicine. Methods: We analyzed somatic alterations of 37 DLBCL tissue or blood samples by a hybridization capture-based NGS panel targeting 188 lymphoma-related genes. Results: Totally, 279 single-nucleotide variants and small insertions or deletions affecting 103 genes were identified, with at least 1 mutation detected in 100% (37/37) of cases. The most frequently mutated genes were those involved in epigenetic modifiers ( DNMT3A, KMT2B and KMT2D), activated signaling ( TYK2, MYD88, NOTCH2 and BCR) and transcription factors/transcriptional regulator ( RUNX1, SPEN, IRF4, KLF2 and ASXL1). Significant co-occurrences were shown between RUNX1 mutations with NOTCH2, IRF4, ARID1A and BCR ( P&lt; 0.05, respectively), BCR and IRF4 ( P&lt; 0.01), etc. Additionally, we analyzed the association of genomic aberrations with clinicopathological features in DLBCL. Patients aged &gt; 60 years harbored less LRP1B mutations than those aged ≤60 years (5.3% vs. 33.3%, P&lt; 0.05). The mutation frequency of TP53 was significantly higher in LDH-high (&gt; 244 U/L) group than that in LDH-low (≤244 U/L) group (40% vs. 6.25%, P&lt; 0.05). Compared with germinal center B-cell (GCB), the mutation frequency of TYK was significantly lower in non-GCB (5% vs. 36.4%, P&lt; 0.05). New potential therapeutic targets ( CREBBP, EP300, EZH2, SMARCB1, CD79A/B, BTK, CARD11, MYD88, THFAIP3, PIK3CA, PTEN and JAK) were identified in 55% (11/20) of newly diagnosed patients and in 41.2% (7/17) of relapsed/refractory patients. Ibrutinib, as a single agent, has demonstrated limited activity in DLBCL with mutant MYD88 and wildtype CD79. In this study, we identified 3 patients with mutant MYD88 and wildtype CD79A/B (8.1%), among whom 2 harbored MYD88 L265P variants and 1 had MYD88 S219C mutation. Conclusions: The utility of mutational profiling may facilitate the identification of potential drug targets, which in turns may represent new therapeutic possibilities.
Improving quality of life by promoting patient-provider communication and optimizing social support using a digital health platform.
Authors: Marlon Garzo Saria, Santosh Kesari
Journal: Journal of Clinical Oncology (2022)

e13622 Background: The patient experience, including symptom burden, is often disease-specific and dependent on host factors, the environment, and the tumor itself. Patients with a previous diagnosis of breast cancer are often subjected to multiple and aggressive treatment modalities compounding the already existing symptom burden related to the disease. Digital health can potentially increase patient engagement, close communication gaps between patients and providers, improve providers’ ability to stratify patient populations and adapt services, enable patients and families to access convenient and cost-effective care, and improve decision-making by patients and providers. The primary purpose of this pilot study was to evaluate if the use of a digital health platform can improve quality of life in patients with breast cancer. Methods: Patients with diagnosis of breast cancer were enrolled in a nonblinded, randomized, controlled trial of a digital health platform in self-reporting and monitoring of cancer and cancer-treatment related symptoms compared with usual care. All participants were asked to register in an online mobile application called CancerLife. This novel cancer social network experience provides patients social support through their care journey while at the same time collects patient-reported outcomes displayed inside reports that they can share with their providers. CancerLife automatically randomized each participant and assigned them to the experimental or control arms. The control arm received usual care provided for in the clinics. This group did not have access to the social network, reports or any other intervention or digital tools associated with CancerLife. Participants were asked to self-report their quality of life using the European Quality of Life Survey (EQ-5) every three weeks. Participants in the treatment arm were asked use the CancerLife at least 1 times per week for up to 24 weeks. Participants were also asked to share their print-out report directly with their care team and were instructed to email the report to their care team via their patient portal. Welch’s Two Sample t-test was performed to measure any statistical difference in the mean scores within each group for each time period. Results: CancerLife users had significant improvements in their scores at 9, 12, and 18 weeks; the improvement at 15 weeks was not significant. By contrast, the control group did not have significant improvements in their scores in any of the time periods. Conclusions: Breast cancer patients who were users of CancerLife’s app have more improvement in their Quality-of-Life Scores than randomly assigned non-users. The improvements seen with the use of CancerLife center on two things: improving communication from patient to physician about symptoms and offering patients social support which creates emotional resiliency. Clinical trial information: NCT03094741.